|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2008.18.7625 on September 8 2008 © 2008 American Society of Clinical Oncology.
Gefitinib Maintenance in Stage III Non–Small-Cell Lung Cancer
Professor of Medicine and Deputy Chair, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX To the Editor: Kelly et al1 recently reported in Journal of Clinical Oncology that gefitinib maintenance after chemoradiotherapy and consolidation chemotherapy was associated with a significant decrease in overall survival (but only a slight decrease in progression-free survival) compared with placebo in stage III non–small-cell lung cancer (NSCLC). They offer potential explanations for this, as do Keedy et al2 in an accompanying editorial. We would like to suggest an additional possible reason for this outcome. The flattening of the NSCLC dose-response curve at higher chemotherapy doses suggests that the most important factor in chemotherapy resistance is deficiency of factors required for efficacy.3 Platinum-resistant cell lines may have decreased expression of a range of transporters that are important for cellular uptake of chemotherapy and nutrients.4 In patients with a variety of resistant tumor types, we assessed tumor expression (by immunohistochemistry) of the copper transporter CTR1, which is also important in platinum uptake. CTR1 expression was significantly lower in tumors of patients who had received either chemotherapy or targeted therapies within the previous 3 months than in tumors of patients with a longer interval off therapy.5 The correlation with time from last chemotherapy or targeted therapy was stronger than the correlation with time from last cytotoxic therapy alone. This leads us to hypothesize that either chemotherapy or targeted therapy may result in a broad reduction in membrane transporters and that this, in turn, may generate broad cross resistance. This could, in part, explain why adding tyrosine kinase inhibitors to chemotherapy did not improve outcome in chemotherapy-naive advanced NSCLC patients6 and might also predict that monoclonal antibodies (that do not require uptake across membranes) might add to chemotherapy even if small molecules did not. If correct, this would also predict that most other currently available small molecules targeting tumor cells will add little to chemotherapy if administered in close temporal proximity. With respect to the study by Kelly et al,1 one might speculate that the gefitinib would do little of value (because the recent chemotherapy would limit its uptake into tumor), while at the same time, it would maintain the downregulation of membrane transporters (thereby rendering the tumors less sensitive to subsequent therapy). Assessing the impact of subsequent therapy on patients in this study could be of interest because the patients in the control arm could potentially have gained far more from subsequent therapy than the patients on the gefitinib arm. The discrepancy between progression-free survival and overall survival outcomes in the study by Kelly et al1 would support this conclusion. It is also interesting that a log-linear plot of the overall survival curve for the gefitinib arm in the study by Kelly et al1 demonstrates a marked convexity in the mid portion (> 20% survival level) that is also evident even on the published linear plot. This suggests to us that some aspect of therapy details is synchronizing patient death. We have previously noted that survival curve convexity is a common observation with combination chemotherapy in advanced NSCLC and proposed that the practice of discontinuing chemotherapy after four to six cycles might account for this apparent synchronization.7 Keedy et al2 questioned whether gefitinib was stimulating tumor growth. We would hypothesize instead that the gefitinib has little activity while it is being administered but the act of stopping it has an impact on what the tumor does subsequently. It could be particularly instructive to look in more detail at therapy and the characteristics of the patients dying along the leading edge of this convexity because these may be the patients most affected. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: David J. Stewart, AstraZeneca Expert Testimony: None Other Remuneration: None NOTES published online ahead of print at www.jco.org on September 8, 2008 REFERENCES
1. Kelly K, Chansky K, Gaspar LE, et al: Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non–small-cell lung cancer: SWOG S0023. J Clin Oncol 26:2450-2456, 2008 2. Keedy VL, Arteaga CL, Johnson DH: Does gefitinib shorten lung cancer survival? Chaos redux. J Clin Oncol 26:2428-2430, 2008 3. Stewart DJ, Chiritescu G, Dahrouge S, et al: Chemotherapy dose-response relationships in non-small cell lung cancer and implied resistance mechanisms. Cancer Treat Rev 33:101-137, 2007[CrossRef][Medline] 4. Liang XJ, Shen DW, Gottesman MM: A pleiotropic defect reducing drug accumulation in cisplatin-resistant cells. J Inorg Biochem 98:1599-1606, 2004[CrossRef][Medline] 5. Stewart DJ, Nunez M, Jelinek J, et al: Tumor CTR1 copper transporter modulation by decitabine (DAC) and relationship to global DNA methylation and time from prior therapy. Proc Am Soc Med Oncol 26:11088, 2008 (abstr) 6. Herbst RS, Prager D, Hermann R, et al: TRIBUTE: A phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non–small-cell lung cancer. J Clin Oncol 23:5892-5899, 2005 7. Stewart DJ: Preliminary assessments using nonlinear regression analysis of semilog survival curve plots to detect and characterize prognostically distinct subgroups in non-small cell lung cancer patients treated with epidermal growth factor receptor tyrosine kinase inhibitors. 12th World Congress on Lung Cancer, Seoul, South Korea, September 2-6, 2007 (abstr C1-02)
Related Correspondence
Related Reply
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
